Xia Tianyang, Guan Weiwei, Fu Jinjuan, Zou Xue, Han Yu, Chen Caiyu, Zhou Lin, Zeng Chunyu, Wang Wei Eric
Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
Department of Cardiology, Daping Hospital, The Third Military Medical University, PR China; Chongqing Institute of Cardiology, Chongqing Key Laboratory of Hypertension Research, Chongqing, PR China.
Biochem Biophys Res Commun. 2016 Jun 3;474(3):599-605. doi: 10.1016/j.bbrc.2016.03.110. Epub 2016 Mar 24.
Tirofiban, a glycoprotein IIb/IIIa inhibitor, is an antiplatelet drug extensively used in patients with acute coronary syndrome (ACS) and exerts an therapeutic effect on no-reflow phenomenon during percutaneous coronary intervention (PCI). Previous studies elucidated the vasodilation caused by tirofiban in the peripheral artery. However, whether tirofiban exerts a vasodilator effect on the coronary artery is unclear. Our present study found that tirofiban induced endothelium-dependent vasodilation in a concentration- and time-dependent manner in the isolated rat coronary artery pre-constricted by 5-hydroxytryptamine (5-HT). Further study showed that incubation of human umbilical venous endothelial cells (HUVECs) with tirofiban increased NO production, which was ascribed to the increased eNOS phosphorylation. This was confirmed by the loss of the vasorelaxant effect of tirofiban in the presence of l-NAME (eNOS inhibitor) and L-NMMA (NOS inhibitor) but not SMT (iNOS inhibitor) on isolated rat coronary arteries. The vasorelaxation was also blocked by the PI3K inhibitors, wortmannin and LY294002, as well as the Akt inhibitor SH-5, indicating the role of PI3K and Akt in tirofiban-mediated vasodilation. Moreover, further study showed that soluble guanylyl cyclase (sGC) inhibitor ODQ, or blockers of potassium channel (big-conductance calcium-activated potassium channel) blocked tirofiban-induced vasodilation of the coronary artery. These findings suggest that tirofiban induces vasorelaxation via an endothelium-dependent NO-cGMP signaling through the activation of the Akt/eNOS/sGC pathway.
替罗非班是一种糖蛋白IIb/IIIa抑制剂，是一种广泛用于急性冠状动脉综合征（ACS）患者的抗血小板药物，对经皮冠状动脉介入治疗（PCI）期间的无复流现象具有治疗作用。先前的研究阐明了替罗非班在外周动脉引起的血管舒张作用。然而，替罗非班是否对冠状动脉具有血管舒张作用尚不清楚。我们目前的研究发现，替罗非班在由5-羟色胺（5-HT）预收缩的离体大鼠冠状动脉中以浓度和时间依赖性方式诱导内皮依赖性血管舒张。进一步的研究表明，替罗非班与人脐静脉内皮细胞（HUVECs）孵育可增加一氧化氮（NO）的产生，这归因于内皮型一氧化氮合酶（eNOS）磷酸化的增加。在离体大鼠冠状动脉上，l-NAME（eNOS抑制剂）和L-NMMA（一氧化氮合酶抑制剂）而非SMT（诱导型一氧化氮合酶抑制剂）存在时替罗非班的血管舒张作用丧失，证实了这一点。PI3K抑制剂渥曼青霉素和LY294002以及Akt抑制剂SH-5也阻断了血管舒张，表明PI3K和Akt在替罗非班介导的血管舒张中的作用。此外，进一步的研究表明，可溶性鸟苷酸环化酶（sGC）抑制剂ODQ或钾通道阻滞剂（大电导钙激活钾通道）阻断了替罗非班诱导的冠状动脉血管舒张。这些发现表明，替罗非班通过激活Akt/eNOS/sGC途径，经由内皮依赖性NO-cGMP信号传导诱导血管舒张。
